1. Field of the Invention
This invention relates to composite dosage forms such as pharmaceutical compositions. More particularly, this invention relates to composite dosage forms comprising at least one active ingredient and having a first portion and a molded second portion which is inlaid.
2. Background Information
Coated tablets, such as film coated tablets, sugar coated tablets, gelcaps, and geltabs are used as solid oral dosage forms, having improved aesthetics, stability and swallowability compared to uncoated tablets. It is particularly useful to provide unique aesthetic features to solid dosage forms to aid with their identification and differentiation in the marketplace. Film coatings and sugar coatings are typically applied by spraying in a rotating pan, and while they may be formulated in a variety of colors, generally only one color can be applied around the entirety of a tablet core. Gelcaps and geltabs have been prepared by dip-coating, enrobing, and shrink-fitting of capsule shells onto the surface of a tablet core. These methods enable the use of multiple colors, however suffer from other limitations.
Film formulations for producing gelcaps and geltabs prepared via enrobing methods such as those disclosed in U.S. Pat. Nos. 5,146,730 and 5,459,983 typically comprises a water-based gelatin preparation having about 45% gelatin and about 9% plasticizer (glycerin and/or sorbitol) by weight. The plasticizer has been reported to play a critical role in such formulations. Low ratios of plasticizer to gelatin result in a brittle coating around the tablet core, while high ratios result in a gelatin coating around the tablet which is flexible and can be peeled from the tablet. If a gelatin coating that adheres to the product core is desired, then gelatin formulations having by-weight compositions of 40 percent to 60 percent gelatin, 5 percent to 12 percent plasticizer, 35 percent to 50 percent water, and colorants and pigments in the range of 0.1 percent to 3 percent should be considered. Glycerin and sorbitol can be used as single plasticizers or in combination with each other. In addition, other sugars and poly-hydroxy compounds can be used as additives and plasticizers. If a tamper-evident gelatin-coated medicine tablet is the desired end product, then the ratio of plasticizer to gelatin in the gelatin formulation should be in the range of about 1:5. The need for such plasticizers at such levels imparts limitations to enrobed dosage forms, including a propensity to absorb moisture, which may compromise the physical and chemical stability of the product, as well adding cost to the formulation.
Another current method for forming a shell (or coating) on a core (or substrate) is that disclosed in WO 01/57144 which utilizes the principles of electrostatic deposition to form the coating. This method suffers from the limitation that at least one of the core or the shell must incorporate one or more “charge control agents”, such as metal salicylates, for example zinc salicylate, magnesium salicylate and calcium salicylate; quaternary ammonium salts; benzalkonium chloride; benzethonium chloride; trimethyl tetradecyl ammonium bromide (cetrimide); and cyclodextrins and their adducts, in an amount from about 1% to about 10% by weight of the shell. Charge control agents often cause an unpleasant taste sensation, and additionally may disadvantageously increase oxidation of the shell in which they are employed.
Other limitations shared by conventional encapsulation and enrobing processes include high cost and complexity, limitations on the thickness of the coating or shell, and the creation of raised seams between capsule halves and/or coatings. It would therefore be desirable to have dosage forms of the present invention, which have enhanced versatility for a number of applications, including dosage forms to deliver pharmaceuticals, nutritionals and/or confections, which may be in the form of geltabs or gelcaps, coated tablets, high potency dosage forms and the like. Moreover, such dosage forms have unique and pleasant aesthetic qualities that are valuable in the marketplace.
It is known to produce coatings on tablets by compression, to produce either multiple stacked layers, or core and shell configurations. Such coatings may have shapes which are substantially independent of the shape of the core, as disclosed for example in WO 00/18447. Commercially available compression coating machines are available for example from Korsch America Inc. (a subsidiary of Korsch AG), and described in WO 89/11968. Modified release dosage forms prepared via compression are exemplified in U.S. Pat. Nos. 5,738,874 and 6,294,200, and WO 99/51209. It is possible via compression-coating to produce a 2-portion shell, which may function as a barrier, or release delaying coating, however compression-coated systems are limited by the shell thickness and shell composition as well as processing costs. Gunsel et al., “Compression-coated and layer tablets” in Pharmaceutical Dosage Forms—Tablets, edited by H. A. Lieberman, L. Lachman, J. B. Schwartz (2nd ed., rev. and expanded Marcel Dekker, Inc.) pp. 247-284, for example, discloses the thickness of compression coated shells is typically between 800 and 1200 microns. Additionally these authors note that “the advent of film coating dissipated much of the advantage of dry coating since larger quantities of tablets can be coated in a short time with film-formers dissolved in organic or aqueous solvents.” Typically, compressed coatings must contain a substantial amount of a compressible material. The compressed shell of WO 00/18447, for example, employs microcrystalline cellulose at a level of about 30%.
Dosage forms having two or more distinct portions are useful in the pharmaceutical arts for overcoming a number of commonly encountered challenges, including the separation of incompatible active ingredients, achieving acceptable content uniformity of a low-dose/high potency active ingredient, delivering one or more active ingredients in a pulsatile manner, and providing unique aesthetic characteristics for dosage form identification. Known methods for achieving a multi-portion pharmaceutical dosage form include particle coating, multi-layer tablets, compression-coating, and spray coating techniques. It is also known for example in the household products industry to assemble solid forms from two or more different parts for the purpose of separating active ingredients, or delivering different active ingredients at different times.
Dosage forms comprising coated particles are described for example in U.S. Pat. No. 5,593,696, which describes oral dosage forms for treating of gastric disorders. The dosage forms contain, as active ingredients, famotidine and sucralfate. In the dosage form, the famotidine is present in the composition in particulate (granulate) form, and the particulate famotidine is provided with a protective barrier layer which prevents interaction between the famotidine and the sucralfate in the composition. The barrier layer is preferably a polymeric coat which dissolves partially in vivo in the stomach environs to release the coated famotidine. U.S. Pat. No. 5,980,944 describes a solid oral dosage form for the treatment of gastrointestinal disorders comprising a therapeutically effective amount of a pharmaceutical suitable for the treatment of gastric disorders selected from the group consisting of granules of diphenoxylate, loperamide, loperamide-N-oxide, pharmaceutically acceptable salts thereof and combinations thereof, and a therapeutically effective amount of simethicone wherein the pharmaceutical and simethicone are separated by a barrier coat on the granules which is substantially impermeable to simethicone.
Multi-layer tablets are described, for example, in U.S. Pat. No. 5,200,193, which describes multi-layered pharmaceutical active tablets comprising an immediate release layer and a homogeneous compressed sustained release layer comprising an erosion promoter, which upon administration results in a long-lasting, slow and relatively regular incremental release of the pharmaceutical active ingredient. U.S. Pat. No. 6,372,252 describes a pharmaceutical sustained release formulation capable of providing therapeutically effective bioavailability of guaifenesin for at least twelve hours after dosing in a human subject. The modified release guaifenesin bi-layer tablet disclosed has a first portion comprising an immediate release formulation of guaifenesin and a second portion comprising a sustained release formulation of guaifenesin. U.S. Pat. No. 4,999,226 discloses a multi-layered tablet containing an ibuprofen layer, a piperidino-alkanol antihistamine layer, and a layer or layers containing conventional pharmaceutical excipients which is interspersed between the ibuprofen and piperidino-alkanol layer and serves to physically separate them. This multi-layered tablet solves the problems associated with the physical and chemical incompatibilities between ibuprofen and the piperidinoalkanol antihistamines. U.S. Pat. No. 4,198,390 describes a tablet containing at least two separate and discrete volume portions, one of which contains simethicone and the other of which contains antacid. A barrier separates the two volume portions to maintain the simethicone out of contact with the antacid and to prevent migration of the simethicone from its volume portion of the tablet into the volume portion containing the antacid, and vice versa. U.S. Pat. No. 5,133,892 describes a multilayer detergent tablet containing an outer layer, a barrier layer and an inner layer. The tablet sequentially releases ingredients contained in the outer layer and ingredients contained in the inner layer. The time interval between the release of the outer layer ingredients and the release of the inner layer ingredients is controlled by the particular choice of an ingredient for the barrier layer and the relative thicknesses of the inner layer, the barrier layer and the outer layer. The tablet is able to separate in time the dissolution of incompatible ingredients such as an enzyme and a chlorine bleach. The tablet also provides sequential release of a dishwashing composition and a rinse aid composition such that cleaning is accomplished prior to the release of the rinse aid.
Compression-coated tablets are useful for separation of incompatible active ingredients, and for pulsatile release of one or more active ingredients. Compressed coatings may have shapes which are substantially independent of the shape of the core, as disclosed for example in WO 00/18447. Commercially available compression coating machines are available for example from Korsch America Inc., a subsidiary of Korsch AG, and described in WO 89/11968. Modified release dosage forms prepared via compression are exemplified in U.S. Pat. Nos. 5,738,874 and 6,294,200, and WO 99/51209. It is possible, via compression-coating, to produce a 2-portion shell, which may function as a barrier, or release delaying coating; however compression-coated systems are limited by the shell thickness and shell composition as well as processing costs. Gunsel et al., “Compression-Coated and Layer Tablets” in Pharmaceutical Dosage Forms—Tablets, edited by H. A. Lieberman, L. Lachman, J. B. Schwartz (2nd ed., rev. and expanded Marcel Dekker, Inc.) pp. 247-284, for example, discloses the thickness of compression coated shells is typically between 800 and 1200 microns. Additionally these authors note that “the advent of film coating dissipated much of the advantage of dry coating since larger quantities of tablets can be coated in a short time with film-formers dissolved in organic or aqueous solvents.” Typically, compressed coatings must contain a substantial amount of a compressible material. The compressed shell of WO 00/18447, for example, employs microcrystalline cellulose at a level of about 30%.
One method for addressing the challenge of low-dose/high potency actives is described for example in U.S. Pat. No. 4,322,449 and U.S. Pat. No. RE 31764, which disclose a method for the preparation of pharmaceuticals which comprises using a piezoelectric dosing system to dot liquid, dissolved or suspended active substance onto a pharmaceutical carrier. The disclosed method enables precise dosing of active pharmaceutical ingredients onto pharmaceutical carriers. The dotting is effected by, for example, use of tubular or plate-shaped piezoelectric dosing systems. However, the liquid, dissolved or suspended active substance can also be divided into discrete droplets of specific volume after application of a high pressure during passage through a narrow nozzle, whereby the individual droplets are successively charged electrically and are intermittently deflected electrostatically towards the pharmaceutical carriers.
The incorporation of molded portions into delivery systems has been used in the household products industry to achieve an additional degree of versatility. Assembled forms comprising a mixture of compressed and molded portions are known for example for delivery of detergents. WO 01/49815 describes a composition for use in a dishwasher characterized by a base composition in the form of a tablet which becomes active substantially during the main wash cycle, and at least one separate zone in or on the tablet is provided with a substance that becomes active substantially during the rinse cycle of the dishwasher. One example of such assembled forms comprises a compressed tablet portion having a hemispherical indentation in a major face, and a molded spherical portion fit into and adhered to the indentation in the compressed portion. One limitation of such assemblies is the propensity for the two portions to become detached due to inadequate adherance and minimal surface area of contact between them. In such assemblies, the molded portion may be smaller than the indentation in the compressed portion, e.g. the diameter of the molded portion is at least about 20 microns less that the diameter of the opening in the compressed portion. Alternatively, similar forms may be assembled by press-fitting. In these forms the dimensions of the molded portion and the opening in the compressed portion may be similar. Such assemblies are additionally limited in the types of geometries that are possible at the interface. In press-fit assemblies, the width of the molded portion at the deepest part of the interface may not be substantially larger than the width of the opening through which it must be fit. In other words the draft angle between the outer and inner surfaces of the compressed portion may not be negative. Moreover, the interface or area of contact between the two portions may not form an interlock.
Another significant opportunity in designing pharmaceutical dosage forms is that of product identification and differentiation. It is useful, both from a consumer safety perspective, and a commercial perspective, to have a dosage form with a unique appearance that is readily recognizable and identifiable.
Current techniques for providing unique dosage form identification include the use of intagliations. Intagliations are impressed marks typically achieved by engraving or impressing of a graphical representation, for example a figure, mark, character, symbol such as a letter, a name, a logo, a pictoral representation, and the like, or any combination thereof, in a tablet or other solid dosage form, preferably by a punching procedure. U.S. Pat. No. 5,827,535, for example, describes soft gelatin capsules having an external surface having defined thereon an impressed graphical representation. U.S. Pat. No. 5,405,642 discloses a method of highlighting intagliations in white or colored coated tablets by spraying onto said tablets a suspension comprising a filling material having a different color, a waxy material and a solvent, and removing the solvent and the excess of filling material and waxy material. The suspension of U.S. Pat. No. 5,405,642 comprises a waxy material and a filling material in a critical weight ratio from about 1:3 to about 1:12. Too little waxy material will lead to insufficient bonding of the filling material; too much waxy material the filling material will bond too strongly to the tablet surface and consequently will be difficult to remove afterwards. Suitable solvents for the suspension of U.S. Pat. No. 5,405,642 are those solvents wherein the filling material and, if present, the dye, do not dissolve. For example, non-dyed starches and celluloses may be suspended in alcohols, e.g. ethanol, isopropanol and the like, halogenated hydrocarbons, e.g. dichloromethane, trichloromethane and the like.
EP 060,023 discloses a method of emphasizing intagliations in colored (i.e. not white) solid articles, in particular tablets, by coating the tablet surface and filling up the intagliations with a coating film comprising an optically anisotropic substance. An optical contrast between the tablet surface and the intagliations is obtained, presumably due to the different orientation of the optically anisotropic substance on the tablet surface and in the intagliations. The technique is limited to colored articles and only allows the use of optically anisotropic filling materials. The optical effect merely being based on a different contrast is not particularly clear.
EP 088,556 relates to a method of highlighting intagliations in white or colored tablets by contacting said tablets with a dry, powdery material having a different color than the tablet surface and then removing the excess powdery material not deposited in the intagliations. The powdery material is thought to adhere better to the intagliations of coated tablets than to those of uncoated tablets. Adherence can further be increased by using a mixture of a wax and a powdery material as the deposition material and heating the filled tablets to 40° C.-90° C. to melt the wax. Finally, an outer coating may be applied to the filled tablets. However, the method disclosed in EP 088,556 has several problems. First, it has been found that the adhesion of the powdery material to the intagliations is not satisfactory as the material shows a tendency to loosen and fall out. This problem arises particularly when an outer coating film is applied to the filled tablet and the loosened material becomes fixed in the outer coating film, thus yielding speckled tablets. Addition of a wax to the powdery material to improve adhesion, on the other hand, adversely affects the distribution of the powdery material in that more of it sticks to the surface of the tablet and is difficult to remove. Several other drawbacks are associated with the use of a wax in the dry powdery material. In particular the necessity to heat the tablets filled with a wax and a powdery material to melt the wax poses a barely acceptable risk since many medicines are thermolabile and might deteriorate significantly in the process. Further, it is difficult to evenly dye a dry mixture of a wax and a powdery material, which in turn puts a limitation on the effectively possible color combinations.
U.S. Pat. No. 4,139,589 describes a process for the manufacture of an inlaid tablet, comprising the steps of incorporating into a plastic chewing gum mass a sustained-release active ingredient; incorporating into a non-plastic tablet mass a substantially immediate-release pharmaceutically active ingredient; and respectively converting the chewing gum mass and the tablet mass into the core and the outer layer of the inlaid tablet. A preferred embodiment includes converting the tablet mass into a recessed preformed element, converting the chewing gum mass into the core, inserting the core into the recess of the preformed element, introducing the preformed element and the core into a tablet mold, and subjecting the preformed element and the core in the mold to pressure.
All of the methods described above for producing a dosage form having one or more separate portions are relatively costly, complex, and time-intensive. Additionally, known methods for producing filled-in intagliations are limited in terms of suitable materials and the obtainable surface configurations and appearance of the resultant dosage form. Besides the above-mentioned limitations on the fill material itself, the tablet subcoating must be non-adhesive enough for the fill-in material to rub off upon tumbling in a hot coating pan. These methods cannot produce filled-in intagliations having the fill material raised above the tablet surface, or even perfectly flush with the tablet surface. The prior art product can only have a fill-in material surface that is slightly depressed, abraided, or concave with respect to the tablet surface.
Another significant challenge in the pharmaceutical industry is the opportunity to minimize manufacturing and packaging costs through standardization. Many drugs are available in several different strength tablets for convenience of dosing different patients with varying needs. Typically, higher strength tablets have greater weight and larger size than tablets having lower amounts of active ingredient. Handling and packaging costs could be reduced by having a dosage form design with the versatility to accommodate multiple different dosage amounts of medication in the same size tablet, yet be readily identifiable to patients and healthcare professionals in terms of identity and strength.
Accordingly, it is one object of this invention to provide a composite form comprising at least one active ingredient, a first portion and a second molded portion comprising a second material, in which the second material is inlaid and compositionally different than the first material.
Other objects, features and advantages of this invention will be apparent to those skilled in the art from the detailed description of the invention provided herein.